The long range objective of the proposed research is the definition at the molecular level of the mechanism(s) involved in drug resistance in Plasmodium, the causative agent of human malaria. This proposal is based on the similarity observed between the drug resistance phenotype of tumor cells and Plasmodium spp. One of the genes involved in tumor cells and protozoa resistant to drugs is the g-glutamylcysteine synthetase (ggcs) gene. We are working with an in vivo rodent malaria model, which includes sensitive strains of P. berghei as well as several lines with different profiles of drug resistance. The specific aim is: To characterize the ggcs homologue gene in drug resistant lines of the murine malaria, P. berghei and drug sensitive and drug resistant lines of the parasite. The working hypothesis is that P. berghei will express the ggcs gene in both sensitive and resistant lines, and that gene amplification and/or gene overexpression is related to the development of the multidrug resistance phenotype. Understanding the mechanisms by which the parasites become resistant will provide the basis for better drug chemotherapy and improved control of this fatal disease.